Genomic Insights into Innate Resistance in Early-Stage EGFR-Mutant Non-Small Cell Lung Cancer: A Comprehensive Analysis of Next-Generation Sequencing Data

Purpose Comprehensive genomic profiling of early-stage non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations remains limited. This study aimed to investigate genomic profiles of early- and advanced-stage EGFR-mutant NSCLC and identify potential innate resistance mechanisms to EGFR-tyrosine kinase inhibitors (TKIs) using targeted next-generation sequencing (NGS). Materials and Methods This retrospective observational study analyzed genomic profiles of patients with early-stage (IA–IIIA) and advanced-stage (IIIB–IV) EGFR-mutant NSCLC from the Lung Cancer NGS registry. Targeted NGS was performed to assess concurrent genetic alterations (GAs), tumor mutational burden (TMB), and variant allele frequency (VAF) of EGFR mutations. Results Overall, 160 patients (100 early-stage and 60 advanced-stage) were analyzed. The proportion of patients with concurrent GAs was not significantly different between stages (82.0% vs. 91.7%, p=0.092). Median TMB was 3.8 mutations/Mb in both stages, with no significant difference (p=0.206). However, the median VAF of EGFR mutations was significantly lower in early-stage compared to that in advanced-stage (19.3% vs. 29.6%, p=0.002). While TMB remained unchanged with disease progression (P = 0.192), VAF of EGFR mutations increased significantly (p<0.001). Moreover, the frequencies of concurrent single nucleotide variants and copy number variants were significantly lower in early-stage NSCLC. Conclusion Genomic heterogeneity in EGFR-mutant NSCLC arises early in tumorigenesis. The comparable TMB and lower VAF of EGFR mutations in early-stage disease suggest that innate resistance to EGFR-TKIs may be driven by concurrent GAs, supporting the consideration of combination therapies even in early-stage EGFR-mutant NSCLC.